Adoptive cell transfer (ACT) therapy using bioengineered T cells continues to show significant promise in the treatment of cancer. To this end, investigators at academic and government centers have tested the concept of chimeric antigen receptors (CARs) in advanced cancer. A CAR is a single unit immune receptor of fixed specificity generally comprised of an extracellular antigen-specific antibody fragment coupled to intracellular T cell-signaling domains (Eshhar et al., 1993, Proc. Natl. Acad. Sci. USA 90:720-724). In recent trials, dramatic eradication of refractory chronic lymphocytic leukemia, where all tumor cells express CD19, was achieved by CD19-specific CAR T cell therapy, where all tumor cells express CD19 (Kochenderfer et al., 2010, Blood 116:4099-4120; Porter et al., 2011, N. Engl. J. Med: 365:725-733). Despite these encouraging results, significant challenges still exist to widespread CAR application. For instance, other tumors are often heterogeneous in antigen expression, differing among individuals, but also in the same patient. Additionally, cancer cells can lose antigen expression by a process of immune-editing, contributing to tumor relapse following initially-effective specific therapy. Targeting a single antigen with CAR therapy may accordingly result in initial tumor regression, but ultimately select for the outgrowth of antigen-loss variants. To facilitate broad clinical application of CARs, scientists have proposed the establishment of a panel of bioengineered T cells with different specificities, custom-made for each individual (Rosenberg et al., 2011, Mol. Ther. 19:1928-1930). Here, each new CAR must be individually created, empirically-tested and produced under clinical-grade conditions; a process that is both technically and economically challenging. The creation of a standardized, distributable immune receptor platform that can be easily tailored for specific antigen-targeting and is amenable to rapid preclinical screening and clinical application would markedly increase accessibility of ACT therapy.
The development of CARs, which bestow T cells with the capacity to recognize cell surface antigens in an MHC unrestricted manner and to receive T cell activation and costimulatory signals, allows for the de novo generation of T cells with potent anti-tumor activity for therapy (Eshhar et al., 1993, Proc. Natl. Acad. Sci. USA 90:720-724). CAR therapy can lead to profound eradication of refractory chronic lymphocytic leukemia and advanced follicular lymphoma, where all tumor cells express, CD19, the target TAA (Kochenderfer et al., 2010, Blood 116:4099-4120; Porter et al., 2011, N. Engl. J. Med: 365:725-733). However, human tumors are often heterogeneous in expression of cell surface antigens, differing markedly not only among individuals but even in the same patient. Further, tumor cells commonly lose cell surface antigen expression during malignant disease progression. Antigen loss is one major factor contributing to tumor relapse following specific therapy that had been initially effective. Alternatively, targeting of TAAs expressed at low levels on normal tissue cells can result in specific toxicity, leading to the retirement of costly vectors. CARs having fixed antigen specificity which are capable of targeting only one TAA may therefore be limited in widespread, continued application as antigen loss variants and toxicity confronted by conventional CAR therapy are not easily addressed by improving binding affinity, cytolytic activity or survival of redirected T cells. Broad application and improved success of CARs in the clinic would necessitate a panel of bioengineered T cells with different specificities, custom-made for each individual. Practically speaking, this approach is technically and economically challenging (Kohn et al., 2011, Mol. Ther. 19:432-438).
Adoptive immunotherapies composed of T cells engineered to express a CAR offer an attractive strategy for treatment of human cancer. However, CARs have a fixed antigen specificity such that only one tumor-associated antigen (TAA) can be targeted, limiting the efficacy that can be achieved due to heterogeneous TAA expression. For this reason, a more generalized and effective application of CAR therapy would benefit from the capability to produce large panels of CARs against many known TAAs.
There is a need in the art for compositions and methods for universal immune receptor (UnivIR) therapies targeting any antigen. The present invention addresses this unmet need in the art.